Greenlab.npih.ucla.edu

Psychopharmacology (2006) 187:312–320DOI 10.1007/s00213-006-0428-x
The neurocognitive effects of aripiprazole: an open-labelcomparison with olanzapine
Robert S. Kern & Michael F. Green &Barbara A. Cornblatt & J. Randall Owen &Robert D. McQuade & William H. Carson & Mirza Ali &Ron Marcus
Received: 26 November 2005 / Accepted: 3 May 2006 / Published online: 30 June 2006
Objectives The present paper is the first report, to our knowl-
Rationale Cognitive deficits are a core feature of schizo-
edge, on the neurocognitive effects of aripiprazole. Unlike
phrenia. As a target of intervention, improvements in
other second-generation antipsychotics, aripiprazole is a D2
cognition may lead to improvements in functional outcome.
and D3 receptor partial agonist. It is unknown what effects thisunusual pharmacological profile may yield on neurocognition.
Materials and methods The present open-label study
Department of Psychiatry and Biobehavioral Sciences,
included data on 169 patients with schizophrenia or
schizoaffective disorder who were randomly treated with
aripiprazole or olanzapine. Subjects received a neuro-
cognitive battery at baseline, week 8, and 26.
VA Greater Los Angeles Healthcare Center (MIRECC 210A),
Results The aripiprazole group had a significantly greater
dropout rate than the olanzapine group. Neurocognitive data
were reduced through a principal components analysis that
yielded a three-factor solution. The factors were general
cognitive functioning, executive functioning, and verbal
learning. For general cognitive functioning, both groups
Mental Illness Research, Education, and Clinical Center,
improved from baseline and the effects were relatively stable
over the 26-week protocol. There were no differential
treatment effects. For executive functioning, neither group
improved significantly from baseline. For verbal learning,
the aripiprazole group improved significantly from baseline
to the 8th and 26th week of assessment, and there was a
between-group effect favoring aripiprazole over olanzapine
North Shore-Long Island Jewish Health System,
that was largely attributable to the differences in performance
within the 8th week. Separate analyses were conducted for a
measure of sustained attention (Continuous Performance
Test–Identical Pairs). There were no differential treatment
Conclusions The findings from this open-label study
R. D. McQuade W. H. CarsonOtsuka America Pharmaceutical, Incorporated,
suggest that the neurocognitive effects of aripiprazole are
at least as good as those of olanzapine.
Keywords Schizophrenia . Aripiprazole . Olanzapine .
Otsuka Maryland Research Institute,Rockville, MD, USA
Neurocognition . Learning . Memory . Dopamine . Agonists
dopamine receptors, behaving as a functional antagonist inhyperdopaminergic states and as a functional agonist in
hypodopaminergic states (Burris et al. Kikuchi et al.
Shapiro et al. ). Aripiprazole exhibits a high
binding affinity for D2 and D3 receptors, a moderate affinity
for D4 receptors, and a low affinity for D1 receptors.
Preclinical studies have also indicated that aripiprazole has
a relatively high affinity for serotonin 5HT2A and 5HT1A
receptors. It displays partial agonist activity at the 5HT1A
receptor and antagonistic activity at the 5HT
(Jordan et al. McQuade et al. ). It is not known
what neurocognitive effects might be expected from an
antipsychotic with this complex mechanism of action. This
paper reports on the results of a multicenter study that
assessed the neurocognitive effects of aripiprazole vsolanzapine using an open-label, randomized study design.
Cognitive deficits are now widely recognized as a corefeature of schizophrenia, largely independent of the psychot-ic symptoms of the illness (Gold The cognitive
Subjects The study included 19 sites and 255 randomly
domains affected include, among others, impairments in
picked patients (aripiprazole=128 and olanzapine=127). All
attention, working memory, verbal and visual learning, speed
patients in the study were outpatients who met the
of processing, language abilities, and reasoning and prob-
Diagnostic and Statistical Manual of Mental Disorders–IV
lem-solving (Aleman et al. Cornblatt et al.
diagnostic criteria for schizophrenia or schizoaffective
disorder, were between ages of 18 and 65, able to speak
Nuechterlein and Dawson ; Nuechterlein et al.
and understand English, were on a stable dose of an oral
Saykin et al. ). It is important to note that there is a
typical antipsychotic, risperidone, or quetiapine for at least
growing awareness that these deficits are linked to impair-
1 month, and had not been hospitalized for psychiatric
ments in community outcome and rehabilitation success
treatment for at least 2 months before randomization.
Exclusion criteria included current suicidality, neurological
A number of reports have examined the effects of second-
disorder (e.g., epilepsy), acute or unstable medical condition,
generation antipsychotic (SGA) medications on cognition in
a clinically significant laboratory test value, gastrointestinal
schizophrenia. Most report advantages when compared with
resection or stapling that may interfere with study medica-
conventional antipsychotic agents (Bilder et al. see
tion absorption, and alcohol- or substance-dependence
Keefe et al. ; Meltzer and McGurk for reviews).
within the past 3 months. Patients were also excluded if
However, there are relatively few replicated findings of
they had received aripiprazole in a prior clinical study, had
specific treatment effects at the domain level (e.g., Green et
taken a selective serotonin reuptake inhibitor within 2 weeks
al. Haggar et al. ; Hoff et al. Kern et al.
before screening, or if they had taken an investigational drug
Lee et al. ; Rossi et al. ). In general, the
within 4 weeks before randomization. Patients were included
effect sizes for SGAs compared with standard doses of
in the analyses if they had a neurocognitive assessment at
conventional agents were small to medium (Woodward et al.
baseline and at least one follow-up assessment (aripipra-
zole=76 and olanzapine=93, total n=169). Table presents
This is the first report, to our knowledge, of the neuro-
the demographic and symptom ratings for the sample,
cognitive effects of aripiprazole. Aripiprazole was shown to
divided according to treatment group. Of the 255 patients
be effective, safe, and well-tolerated for the treatment of
enrolled in the study, 109 (43%) completed the entire 26-
positive and negative symptoms in persons with schizophre-
week protocol [60 subjects (47%) from the olanzapine group
nia and schizoaffective disorder (Potkin et al. and to
and 49 subjects (38%) from the aripiprazole group]. Of the
have a low liability for extrapyramidal side-effects and a low
146 patients who discontinued the study, 21 were lost to
incidence of clinically significant weight gain (Marder et al.
follow-up, 23 withdrew consent for personal reasons, 46
McQuade et al. It has a unique pharmacology
discontinued due to adverse events, 39 discontinued due to
among SGAs in that it is a partial agonist at D2 and D3
lack of clinical response or worsening of clinical symptoms
of schizophrenia, 13 were excluded for noncompliance, and
At baseline, subjects were administered the North
4 were excluded for violation of protocol. The overall
American Adult Reading Test (NAART; Blair and Spreen
difference in dropout between aripiprazole and olanzapine
), a widely used measure of premorbid intelligence. In
was attributable to differences in the number of subjects who
addition, subjects were administered the Vocabulary, Block
discontinued the study due to personal reasons (14 vs 9),
Design, and Information subtests from the Wechsler Adult
adverse events (25 vs 21), lack of clinical response (22 vs
Intelligence Scale (WAIS III; Wechsler to measure
17), and medication noncompliance (9 vs 4); not because of
lost to follow-up (8 vs 13) or protocol violations (1 vs 3).After complete description of the study to the subjects,
written informed consent was obtained.
The study was designed to assess short- and longer-term
The neurocognitive tests used in the study are as follows:
neurocognitive treatment effects and included a baselineand two postbaseline assessments scheduled at 8 and
1. California Verbal Learning Test (CVLT; Delis et al.
26 weeks after randomization (1:1 ratio) to either 30 mg
). The CVLT is a test of learning and memory. A
of oral aripiprazole or 15 mg of oral olanzapine (olanza-
16-item list is presented over five learning trials with
pine-treated patients received 10 mg for the first 7 days and
recall assessed after each trial. After the fifth trial, a new
15 mg from day 8 onwards). The selection of the
list of 16 items is presented and recall assessed. Tests of
olanzapine dosing regimen was based on published clinical
cued and free recall for the first list are administered
efficacy data (Beasley et al. and clinical practice at
after short and long (20 min) delays. After the long delay
the time of the initiation of the study. Randomization was
recall, a 44-item recognition test is administered. The
stratified according to prior antipsychotic therapy (conven-
same form was used across assessment points. The
tional vs atypical). Administration of nonstudy antipsychot-
dependent measures selected for the current study were:
ic medications was prohibited during the course of the
(1) list A trials 1–5 total recall (a measure of learning),
study. However, prior antipsychotic medications could be
(2) semantic clustering ratio (a measure of learning
tapered during the first 2 weeks of the study protocol to
strategy), and (3) the discriminability index (a measure
prevent destabilization. Patients on mood stabilizing med-
ications before the onset of the study were maintained on
2. Benton Visual Retention Test–Revised (BVRT-R;
these medications during the study. Anxiolytic medications
Benton ). The BVMT-R is a test of visual memory.
(e.g., lorazepam) were permitted for use during the study
The subject is shown ten cards that contain abstract
for treatment of anxiety or insomnia. Twenty-one percent of
geometrical designs. After presentation of each card,
aripiprazole patients compared with 10% of olanzapine
the subject is asked to draw it from memory. The test
patients received anxiolytic medication as a concomitant
includes different administration conditions. For the
treatment. Anticholinergics (e.g., benztropine) were tapered
current study, Administration A was used. This admin-
and discontinued by the end of the second week of study
istration involves a 10-s exposure with no delay. The
treatment. At baseline, 12% of olanzapine patients and 10%
test includes three alternate forms that were counter-
of aripiprazole patients were receiving anticholinergic
balanced across assessment points. The dependent
medications for treatment of extrapyramidal symptoms
(EPS). During the study, EPS were treated with medications
3. Wisconsin Card Sorting test (WCST; Heaton et al.
other than anticholinergics (e.g., propranolol). Administra-
). The WCST is a test of concept formation and the
tion of antidepressant agents was prohibited after random-
ability to maintain and shift cognitive set. The comput-
ization. At baseline, 12% of both olanzapine and
erized version used in the present study measures the
aripiprazole patients were receiving antidepressant medica-
ability of subjects to match a deck of stimulus cards to
tion. Patients who elected to discontinue the study before
one of four key cards. The cards can be matched
completion of the 26-week trial were administered the
according to color, shape, or number of figures. Subjects
neurocognitive battery at the time of departure.
are provided little instruction about how to match thecards; only whether their attempt(s) were correct or not.
Procedure Neurocognitive and symptom assessments were
Unbeknownst to the subject, the correct sorting rule
conducted at baseline, week 8, and week 26. The neuro-
changes after ten correct matches and the subject must
cognitive battery assessed areas commonly impaired in
adjust their sorting strategy to the new matching rule.
schizophrenia and included measures of attention, memory,
The present protocol used an abbreviated 64-card
executive functioning, and manual dexterity. The battery
version. The primary dependent measures were (1)
required approximately 90 min of administration time and
number of categories, (2) percent conceptual level
responses, and (3) percent perseverative errors.
4. Trail Making A and B (Army Individual Test Battery
each of the two conditions. The primary dependent
). This test measures fine motor speed, visual
measure for each condition was d-prime, which
search, and the ability to alternate cognitive set. In Part
indicates the response sensitivity for discrimination of
A, subjects are asked to connect as quickly as possible a
series of circled numbers that are haphazardly located ona sheet of paper. The numbered circles are to be
connected in ascending order. Part B is similar to Aexcept that some circles contain numbers and others
Severity of psychiatric symptoms was measured using the
letters. The subject is instructed to connect the circles by
Positive and Negative Symptom Scale (PANSS; Kay et al.
alternating between numbers and letters (e.g., 1-A-2-B-
). The PANSS includes three scales: positive scale,
3-C and so on). The dependent measures for Parts A and
negative scale, and general psychopathology scale. The
positive scale items include delusions, conceptual disorgani-
5. Verbal fluency (letter and category; Spreen and Benton
zation, hallucinations, excitement, grandiosity, suspicious-
Tests of verbal fluency assess verbal productiv-
ness, and hostility. The negative scale items include blunted
ity under selected search conditions. For the current
affect, emotional withdrawal, poor rapport, passive pathetic
study, verbal fluency was assessed under two condi-
withdrawal, difficulty in abstract thinking, lack of spontaneity
tions. In the letter (phonological) fluency condition,
and flow of conversation, and stereotyped thinking. The
subjects were asked to generate as many words as
general psychopathology scale includes items for somatic
possible that begin with a certain letter of the alphabet
concern, anxiety, guilt, tension, mannerisms and posturing,
(e.g., F, A, and S). In the category (semantic) fluency
depression, motor retardation, uncooperativeness, unusual
condition, subjects were asked to generate as many
thought content, disorientation, poor attention, lack of
exemplars of a particular category (e.g., animals, fruits,
judgment, disturbance of volition, poor impulse control,
and vegetables). All trials were 1 min in length. The
preoccupation, and active social avoidance. The dependent
dependent measure was the total number of correct
measure was change from baseline for the PANSS total score.
words generated across the two conditions.
6. Letter–Number Sequencing subtest from the WAIS-III
(Wechsler ). This test of auditory working memoryincludes two conditions. In the first condition (without
reordering), subjects are presented strings of letters andnumbers of increasing length and asked to repeat them
Statistical analyses were performed using Statistical Analysis
back in the same order. The numbers/letters are
System (SAS Data were initially examined for
presented at the rate of approximately 1 s−1. In the
normality of distribution and where violations occurred
second condition (with reordering), strings of numbers
transformations were performed. The neurocognitive data
and letters are again presented, but this time subjects
were reduced by means of a principal components analysis
are asked to reorder them, first by saying aloud the
(PCA) with the resultant factor scores used as the primary
numbers in their ascending order and then the letters in
outcome variables in the analyses. Data from the CPT-IP had
alphabetical order. The dependent measures were
a relatively large amount of invalid and missing data due to
number of correct items/responses for each condition.
technical and administrative problems at a subset of the sites.
7. Grooved Pegboard test (Matthews and Klove ).
Because PCA requires complete cases for meaningful
This test measures manual dexterity. The subject is
results, these data for the CPT-IP were analyzed separately.
instructed to insert a series of grooved metal pegs into a
We conducted two initial analyses to address the cognitive
metal template with corresponding grooved slots as
effects of aripiprazole vs olanzapine, and then two specific
quickly as possible. Administration includes trials for
follow-up analyses to consider the effects of clinical state
right and left hand performance. The dependent
and dropout on the study results. The primary analytic
measure was time of completion for the dominant hand.
approach was the last observation carried forward (LOCF)
8. Continuous Performance Test–Identical Pairs version
procedure, which was the original analytic plan and the way
(CPT-IP; Cornblatt et al. ). The CPT-IP is a
the data were presented at conferences. The data were then
computerized measure of sustained attention. Subjects
reanalyzed using a mixed model procedure for repeated
are asked to respond to target stimuli that are flashed
measures analysis of variance (Gueorguieva and Krystal
briefly on a computer screen by lifting up their finger
to confirm the LOCF results. Baseline factor scores
from a mouse pad whenever a number repeats itself.
were entered as covariates. Efficacy was assessed by
For the current study, the two- and four-digit conditions
examining within- and between-group contrasts on the
were used. Three hundred trials were administered for
resultant factor scores at the weeks 8 and 26 assessments.
Table 2 Factor structure for neurocognitive battery
Letter–no. sequencing (without reordering), total correct
Letter–no. sequencing (with reordering), total correct
Verbal Fluency (total score for phonologic+semantic conditions)
Highest factor loadings for each variable appear in bold face type.
Treatment group changes in psychiatric symptoms and
differential rates of attrition are sources of variance thatcould confound interpretation of study results. To address
Examination of scores for normality of distribution showed
the contribution of symptom changes, the LOCF analyses
the Trail Making A and B scores to be negatively skewed.
were reconducted with the PANSS total score entered as a
These scores were subsequently transformed using a log
time-varying covariate. To address the effects of attrition,
transformation. The neurocognitive battery included 13
we first examined group differences in dropout (i.e.,
selected variables. To condense the data and reduce Type I
subjects with baseline plus at least one postbaseline
error, we performed a PCA (Nunnally ). Factors
assessment) using chi-square analyses. In response to the
yielding eigenvalues greater than 1.00 were retained (i.e.,
differential dropout rates, the data were then reanalyzed
they extracted at least as much as the equivalent of one
using propensity score weighting (Hirano et al.
original variable; Gorsuch Kaiser for varimax
(orthogonal) rotation. The results of the PCA yielded a three-
The propensity-weighting method is based on the
factor solution. The resultant factors were labeled general
assumption that subjects remaining in a study share, to
cognitive functioning (factor 1), executive functioning
differing degrees, characteristics with those who drop out,
(factor 2), and verbal learning (factor 3; see Table ). A
and these characteristics or predictor variables can be used
number of neurocognitive variables including measures of
to weigh scores to assess possible biasing effects of
visual memory, manual dexterity, verbal recognition memo-
dropout. Propensity weighting involves a two-step process.
ry, working memory, verbal fluency, and psychomotor speed
First, logistic regression is used to identify variables that
loaded on the general cognitive functioning factor. This
predict dropout and generate predicted probabilities for
factor accounted for approximately 40% of the overall
each case remaining in the study. Second, the analyses are
variance. The remaining two factors loaded primarily on
done using the inverse of these probabilities as case
two measures, the WCST and CVLT, respectively. These
weights. Cases who remained in the study, but whose
factors best represent individual measures and the method
propensity scores indicate they were “likely to drop out” are
variance tied to those measures. Consistent with the data
thus similar to those who actually did drop out. Such cases
reduction purpose of these analyses, the factor labels were
are therefore weighted more heavily in the analyses. In the
used to facilitate presentation of results and not to identify
current study, demographic and baseline neurocognitive
constructs. Factors 2 and 3 accounted for an additional 13
factor scores were examined in the first step to determine
and 9% of the overall variance, respectively.
their relationship to dropout. Variables yielding a p value
Initially, the data from the two treatment groups were
<0.10 were retained in the logistic regression. The logistic
examined for baseline comparability on demographics,
regression model generated predicted probabilities for
symptoms, measures of current and premorbid intellectual
remaining cases (propensities). The inverse of those
functioning, and baseline scores from the neurocognitive
propensities, rescaled so that the sum of weights in each
battery (Table ). The two groups were comparable in their
treatment group equaled one, were then used as case
demographic characteristics, premorbid and current intel-
weights in the propensity-weighted data analyses.
lectual functioning, and symptom severity ratings.AriprazoleOlanzapineChange from baseline General CognitiveExecutiveVerbal LearningFunctioningFunctioningSignificant Improvement from baselineSignificant difference between groups
The results from the LOCF analyses are illustrated in
df=1,166, and p=0.027). Follow-up of between-group
Fig. An increase in factor score value indicated
contrasts at the assessment points revealed the group
improvement in neurocognitive functioning. For factor 1
difference to be due largely to a significant difference
(general cognitive functioning), both aripiprazole and
favoring aripiprazole at week 8 (F=5.58, df=1,166, and
olanzapine showed significant improvement from baseline
p=0.019) that was smaller and nonsignificant at week 26. In
at week 8 (p=0.023 and 0.015, respectively) that fell to a
sum, both the LOCF and mixed model analyses showed
trend at week 26 (p=0.055 and 0.087, respectively). There
within group improvement from baseline for aripiprazole at
were no significant between-group differences at either
the weeks 8 and 26 assessment points and both analyses
week 8 or 26 comparisons. Results from the mixed model
showed a significant group difference favoring aripiprazole.
analyses were similar to the LOCF analyses. Both groups
The LOCF analyses indicated a more stable pattern over
showed improvement from baseline to week 8 (aripipra-
the 26-week period, whereas the more conservative
zole: t=2.29, df=166, and p=0.024; olanzapine: t=2.68,
mixed model analyses indicated group differences only at
df=166, and p=0.008), and there were no overall group
differences (F=0.00, df=1,166, and p=0.99). The primarydifference in the results for the mixed model analyses was
that the group trends for improvement at week 26 seen in
data from the two conditions of the CPT-IP were analyzed
the LOCF analyses were no longer evident.
separately. For the two-digit condition, the results of the
For factor 2 (executive functioning), the results from the
LOCF analyses on the smaller CPT-IP data set indicated a
LOCF analyses failed to show significant improvement
significant improvement from baseline for aripiprazole at
from baseline to week 8 or 26 for either group (all p>0.20)
week 8 (p=0.034) and week 26 (p=0.027); but no
and there were no between-group differences. The results
significant changes for olanzapine. There were no differen-
from the mixed model analyses yielded the same findings.
tial treatment effects at either week 8 or 26. For the four-
For factor 3 (verbal learning), the results from the
digit condition, there were no significant within- or
LOCF analyses revealed that aripiprazole showed a
between-group effects for either aripiprazole or olanzapine
significant improvement from baseline at both week 8
(all p>0.30). For the mixed model analyses of the two-digit
(p<0.0001) and week 26 (p<0.0001); olanzapine did not.
condition, aripiprazole showed a significant improvement at
Examination of between-group differences at these assess-
week 8 [t(109)=2.74 and p=0.007] that was weaker and
ment points revealed a significant difference in favor of the
nonsignificant at week 26 (p=0.16). There were no
aripiprazole group compared to the olanzapine group at
both week 8 (p=0.020) and week 26 (p=0.040). For themixed model analyses, aripiprazole showed a significant
Analyses with PANSS as time-varying covariate When the
improvement from baseline at both week 8 (t=4.94, df=166,
LOCF analyses of the factor scores and CPT data were
and p<0.0001) and week 26 (t=3.02, df=166, and p=0.003);
conducted with the PANSS total score entered as a time-
olanzapine showed a trend at week 8 (t=1.96, df=166,
varying covariate for weeks 8 and 26 assessment points, the
and p=0.052) but no significant improvement at week 26
results remained essentially the same. That is, the signifi-
(p>0.25). There was a significant overall effect of
cant results remained significant and nonsignificant results
group favoring aripiprazole over olanzapine (F=4.97,
Propensity-weighted analyses A chi-square analyses of
schizophrenia and is frequently used in studies of neuro-
treatment group×dropout indicated a significant overall
cognitive predictors of functional outcome (Green ;
effect (χ2=4.08 and p=.043), indicating greater dropout
Green et al. Performance gains associated with
for the aripiprazole group relative to the olanzapine group.
olanzapine treatment on this list learning measure were
Examination of predictor variables indicated that older age,
more modest than that noted in other studies (Harvey et al.
male gender, and lower scores on the baseline neuro-
; Purdon et al. ; Stip et al. The perfor-
cognitive executive functioning factor were the strongest
mance differences may be linked to differences in the
predictors of dropout. To assess whether the differential
measures, characteristics of the samples, dosing levels, or
treatment effect favoring aripiprazole on the verbal learning
length of treatment, and may have contributed to the
factor was influenced by dropout, propensity weighted
magnitude of the effect size favoring aripiprazole in the
scores were calculated for this factor and these scores were
current study. It should also be noted that the group
entered into a mixed model analyses. The overall group
difference favoring aripiprazole over olanzapine in the
effect favoring aripiprazole vs olanzapine remained signif-
mixed model analyses was largely due to differences at
icant (F=4.80, df=1,166, and p=0.030). Like the mixed
week 8 that were smaller and nonsignificant at week 26.
model analyses without the propensity weightings, the
The waning strength of effects may be due to declining
overall group effect was largely due to group differences
sample size or changes in the composition of the sample.
at week 8 (F=5.81, df=1,166, and p=0.017) that were
The difference between the LOCF and mixed model
smaller and nonsignificant at week 26.
analyses may be due to larger performance differencesbeing carried forward in the LOCF analyses compared withthe parameter estimates used for missing cases in the mixed
Higher levels of performance on list learning measures
The primary aim of this open-label study was to compare
such as the CVLT are linked to better community outcome,
the neurocognitive effects of aripiprazole vs olanzapine in
better social problem-solving ability, and rehabilitation
schizophrenia and schizoaffective disorder outpatients over
success (Green et al. ). There is optimism in the field
a 26-week protocol. In general, the findings revealed
that improvements in cognition such as verbal learning will
aripiprazole and olanzapine to be comparable in their
lead to improvements in real world functioning. However, it
effects on neurocognition. On a factor that represented
is unknown whether changes in cognition will lead directly
general cognitive functioning, and accounted for most of
to improvements in functional outcome in patients with
the variance in the overall battery, both the aripiprazole
schizophrenia. It may be more likely that changes in
group and the olanzapine group showed small but signif-
cognition will enable patients to acquire component skills
icant improvements from baseline that were relatively
(e.g., coping strategies and communication skills) necessary
stable over the 26-week period. The two other factors,
to succeed in the workplace or social environments, and the
executive functioning and verbal learning, that loaded
incorporation of these skills in their daily lives will lead to
primarily on the WCST and CVLT, respectively, accounted
improvements in work and social functioning.
for much less of the variance in the neurocognitive battery.
The study yielded a differential dropout for the two
For the executive functioning factor, neither treatment
drugs with more patients dropping from the aripiprazole
group showed significant improvement from baseline or
than the olanzapine group. The differences in dropout may
any differential treatment effects. For the verbal learning
be due to differences in dose-related side effects (e.g.,
factor, aripiprazole showed a differential treatment effect
restlessness) or other random factors, but may be due to the
compared to olanzapine that was primarily accounted for by
open-label nature of the study and the possibility that
differences at week 8. For the separate analyses conducted
clinicians had a lower threshold for removing subjects from
on the measure of sustained attention, no differential
the arm with an investigational drug (aripiprazole was not
an FDA-approved antipsychotic medication at the time of
Regarding the differential treatment effect on verbal
the study). The 30-mg/day of aripiprazole dose may have led
learning, the magnitude of the effect size for aripiprazole vs
to some of the excess dropout in this group. Premarketing
olanzapine was modest, falling in the small to medium
studies do not suggest any additional clinical benefit from
range (d=0.36; Cohen ). The two CVLT variables that
doses above 15 mg/day, and the higher dose may have been
loaded highest on this factor included the ability to acquire
associated with increased side effects. It is not possible to
new verbal information (total recall trials 1–5) and the use
know for sure what the results would have yielded had
of efficient organizing strategies to facilitate recall (seman-
dropout for the two drugs been comparable. However, when
tic clustering ratio). The CVLT total recall measure is a
the effects of dropout were estimated in the statistical analyses,
commonly used measure to assess verbal learning in
the primary findings on cognition remained the same.
The primary finding from this open label study is that
design. Given the suggestion for a treatment-related
aripiprazole is at least as good as olanzapine on general
difference in verbal learning, future studies may wish to
cognitive functioning, executive functioning, and attention,
target this neurocognitive domain using a more specialized
and may be better at improving verbal learning. Interpretation
battery aimed at assessing a wide range of memory-related
of the results on verbal learning requires consideration of a
processes. If replicated, these findings would suggest that
number of potential confounds. First, the open-label nature of
the D2 partial agonism of aripiprazole might have specific
the study should be considered. Findings from open-label
cognitive benefits compared with the full antagonism of
studies deserve a more conservative interpretation than double-
blind studies. However, it is not obvious how a potential biasor difference in expectation would lead to a differential
The authors would like to thank the patients
and staff of the participating hospitals and clinics who made this study
treatment effect in one cognitive domain, but not the others.
possible. Dr. Kern, Dr. Green, and Dr. Cornblatt have served as
Second, the differential treatment effect could be related to
consultants for Otsuka America Pharmaceutical and Dr. Green and
differential effects of the two drugs on psychiatric symptoms.
Dr. Cornblatt have also served as consultants for Bristol-Myers Squibb
However, the results were unchanged when the PANSS total
Company. Dr. Kern, Dr. Green, and Dr. Cornblatt received no funds orother compensation for preparation of this manuscript. The data
score was entered as a time-varying covariate in the analyses.
analyses were conducted by Jim Mintz, Ph.D., UCLA Department of
Third, group differences at baseline could potentially bias the
Psychiatry and Biobehavioral Sciences and Department of Veterans
results in favor of one group over the other. Here, randomi-
Affairs VISN 22 MIRECC. Funding for this research study was
zation procedures resulted in the two groups being comparable
provided by Otsuka America Pharmaceutical.
across demographic, clinical, and neurocognitive variables atbaseline. In addition, the contribution of baseline neuro-cognitive functioning was addressed in the analyses byentering baseline neurocognitive factor scores as covariates.
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